Project Summary/Abstract More than 40 million Americans currently take statins for the treatment or prevention of hyperlipidemia and cardiovascular disease (CVD). Statin therapy is not without risk. Complications include mild to moderate skeletal muscle adverse reactions, with reported incidence as high as 25%. In addition, statins have been shown to worsen insulin resistance and increase risk for type 2 diabetes. Disturbances in mitochondrial respiratory function have been implicated as a causal factor in these pathologies, but studies to test these potential links have not been conducted in human subjects undergoing statin therapy. Patients taking statins are also commonly advised to exercise regularly to further lower the risk for metabolic and cardiovascular disease. However, recent evidence suggests that statins can impair important exercise adaptations, and that this, again, may occur as a result of statins negatively impacting mitochondria in skeletal muscle. In summary, understanding how long-term statin therapy affects mitochondrial function in skeletal muscle is extremely important clinically, given the critical role skeletal muscle plays in maintaining metabolic and cardiovascular health. Therefore, the objectives of this application are to determine the impact of statin therapy on skeletal muscle mitochondrial function, cardiorespiratory fitness, and metabolism in humans. Aim 1 will use a longitudinal, repeated measures design to test impact of placebo, 20, and 80 mg/day of atorvastatin therapy on skeletal muscle mitochondrial function, insulin sensitivity, and cardiorespiratory fitness. Aim 2 will determine whether 20 and 80 mg/day of atorvastatin differentially blunt the mitochondrial, metabolic, and cardiorespiratory adaptations to aerobic exercise training. State-of- the-art human studies will be conducted in collaboration between two institutions and will include: comprehensive evaluation of mitochondrial function and content, insulin sensitivity, cardiovascular function, and cardiorespiratory fitness. These studies will provide mechanistic data on statin effects in- vivo and improve clinical knowledge of the cost-to-benefit ratio of statin therapy.